CN1169768C - (4-alkynyl), aromatic keto-acid compound, synthesis method and its application - Google Patents

(4-alkynyl), aromatic keto-acid compound, synthesis method and its application Download PDF

Info

Publication number
CN1169768C
CN1169768C CNB02111515XA CN02111515A CN1169768C CN 1169768 C CN1169768 C CN 1169768C CN B02111515X A CNB02111515X A CN B02111515XA CN 02111515 A CN02111515 A CN 02111515A CN 1169768 C CN1169768 C CN 1169768C
Authority
CN
China
Prior art keywords
acid
halogenophenyl
oxidation
alkynyl
replaces
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB02111515XA
Other languages
Chinese (zh)
Other versions
CN1380279A (en
Inventor
马大为
丁克
叶其壮
李佳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS, Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CNB02111515XA priority Critical patent/CN1169768C/en
Publication of CN1380279A publication Critical patent/CN1380279A/en
Application granted granted Critical
Publication of CN1169768C publication Critical patent/CN1169768C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a compound of (4-ynyl)-aromatous ketonic acid, a synthetic method and an application thereof, and the compound has a structural formula 1, wherein R is an alkyl radical pf H or C(1 to 10), and R<1> is an alkyl radical of H, C(1 to 10) or CH2OR<5>; R<2> is a straight chain of H or C(1 to 10) or an alkyl radical with branched chains, and R<3> and / or R<4> is H, OH, OR<5> or NHCOOR<5>; R<5> is an alkyl radical of C(1 to 10), and the alkyl radical is an alkyl radical with a straight chain, an alkyl radical with branched chains or aromatic radicals, an aromatic radical or a substituted aromatic radical. The present invention can be used as an inhibitor of stromatin enzymes, and therefore, the present invention is possible to be used for curing diseases of cancer, arthritis, canker of organism, pneumonectasis, atherosclerosis of blood vessel, etc.

Description

(4-alkynyl)-aryl ketones acid compounds, synthetic method and application
Technical field
The present invention relates to (4-alkynyl)-aromatic ketone acid compounds, synthetic method and application thereof.This compound can be used as the inhibitor of stromatin enzyme, thereby might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
Background technology
Matrix metalloproteinase (matrix metalloproteinases, MMPs) be the zinciferous endopeptidase of gang, all main components that can the degradation of cell epimatrix, thereby participate in renewal (the Ryoichi Hirayama of reticular tissue, Minoru Yamamota.Bioorg.Med.Chem.1997,5,765).Studies show that, some hypotype of MMP is that the human body normal physiological activity is necessary, the other hypotype is then being played the part of extremely important role in some pathology process, as transfer and (Schwartz, the M.A. such as diffusion, multiple arteriosclerosis of osteoarthritis, tumour; Van Eart, H.E.Prog.Med.Chem.1992,29,271).The overexpression meeting of these enzymes causes a large amount of disorders such as cancers, sacroiliitis, body ulcer, generations such as pulmonary emphysema, blood vessel scleratheroma.Therefore, as the target enzyme, it is one of problems of making earnest efforts of Pharmaceutical Chemists during the last ten years that development matrix metallo-proteinase inhibitor (MMPI) is treated these diseases with MMPs.These inhibitor are different with the mechanism of action by structure, can be divided into succinyl-hydroxy acid class, sulphonyl ammonia hydroximic acid, carboxylic-acid etc.
Wherein the carboxylic-acid matrix metallo-proteinase inhibitor is because its high selectivity to each type matrix metalloproteinase more and more is subjected to the attention of various countries' Pharmaceutical Chemist.
Summary of the invention
The object of the invention provides a kind of (4-alkynyl)-aryl ketones acid compounds.
The object of the invention also provides a kind of synthetic method of above-mentioned (4-alkynyl)-aryl ketones acid compounds.
Another purpose of the present invention provides a kind of application of above-mentioned (4-alkynyl)-aryl ketones acid compounds.
Related (4-alkynyl)-aryl ketones acid compounds carboxylic-acid stromatin enzyme inhibitors among the present invention, novel structure shows that through determination of activity a part in them has the abilities that potent and selectivity suppress the different subunits of matrix metalloproteinase.Might be used to treat cancer, sacroiliitis, body ulcer, diseases such as pulmonary emphysema, blood vessel scleratheroma.
(4-alkynyl)-aryl ketones acid compounds of the present invention has following structural formula:
Wherein R is H or C 1-10Alkyl; R 1Be H, C 1-10Alkyl, CH 2OR 5, CH 2OH, OBn, OH or OCH 3R 2Be H, C 1-6Straight chain or have the alkyl of side chain; R 3Or/and R 4Be H, OH, OR 5, NHCOOR 5, C 2H 5Or Ph; R 5Be C 1-10Alkyl; Described alkyl is straight chained alkyl, have the alkyl of side chain or aryl, aryl or substituted aryl.
As following compound is example:
But the synthetic method classified description of compound of the present invention is as follows:
R 2And/or R 3The compound that replaces for chirality synthetic: with R 2And/or R 3The Succinic Acid lactone that chirality replaces is a starting raw material, in polar organic solvent and under the Lewis acid effect, and the R that chirality replaces 2And/or R 3Succinic Acid lactone, halogeno-benzene and lewis acidic mol ratio are 1: the Fu Ke acidylate, backflow 16-36 hour, take place and generate R in 1-1.5: 3-7 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces; Perhaps resterification gets corresponding R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality replaces.Reaction formula is as follows:
Figure C0211151500082
For R 2And/or R 3The meso compound that replaces has following two kinds of methods:
The one, with halogeno-benzene and
Figure C0211151500083
Be raw material, Lewis acid is a catalyzer, and under the room temperature, reaction is 16-24 hour in the organic solvent, generates molecular formula and is
Figure C0211151500084
Halogenophenyl ketone, wherein halogeno-benzene, With lewis acidic mol ratio be 1: 1-2: 1-3; At-78 ℃-room temperature and C 1-8The lithium alkylide effect under, 4-halogenophenyl ketone and alpha-halogen acid esters generation alkylated reaction reacted 5-20 hour, obtained R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces, wherein 4-halogenophenyl ketone, alpha-halogen acid esters and C 1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0.This reaction is preferably under the anhydrous and oxygen-free condition He in the tetrahydrofuran solution to be carried out.
R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid resterification that replaces gets corresponding R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
Described C 1-8Lithium alkylide can be butyllithium, dibutyl lithium, di-isopropyl lithium (LDA), octyl group lithium etc.
The 2nd, the Fu Ke acidylate takes place in the same condition of halogeno-benzene and halo acetyl halide, generates halo ethanoyl halogenophenyl ketone; Halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester PhCH (C 2H 5) the same generation alkylated reaction under the COOR anhydrous and oxygen-free condition, promptly at-78 ℃-room temperature and C 1-8The lithium alkylide effect under, react and obtained R in 5-20 hour equally 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces.Wherein halo ethanoyl halogenophenyl ketone, two substituted acetic acid ester and C 1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0.This reaction be preferably under the anhydrous and oxygen-free condition and tetrahydrofuran solution in.Perhaps resterification gets corresponding R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.Reaction formula is as follows:
Figure C0211151500092
Above-mentioned R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyro-esterification that replaces is by R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that replaces and saturated alcohol roh/hydrochloric acid room temperature reaction 1-10 hour can become corresponding R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
In organic polar solvent, R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces, corresponding alkynes CH ≡ CR 1, contain the organic compound acid binding agent and the catalyzer of lone-pair electron on the nitrogen, 4 alkynyls are introduced in 50-100 ℃ of reaction 16-36 hour, gamma-carbonyl group benzenebutanoic acid ester cpds that must the 4-alkynyl substituted R wherein 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester, the alkynes CH ≡ CR that replace 1With the mol ratio of acid binding agent be 1: 1-3: 0.01-0.15, the weight ratio of 4-(4-halogenophenyl)-4-oxidation-butyric ester and catalyzer is 1: 0.001-0.010, described catalyzer are dichloro two triphenyl phosphorus palladiums, cuprous iodide, tetrabutylammonium iodide or their mixture.The organic compound acid binding agent that contains lone-pair electron on the described nitrogen is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.
Above-mentioned R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and acidifying gets corresponding R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces.
Figure C0211151500101
In aforesaid method, R, R 1, R 2, R 3, R 4Or R 5As previously mentioned.
(4-alkynyl)-aromatic ketone acid compounds of the present invention is simple synthetic method not only, and their inhibition activity have been tested to three kinds of stromatin enzymes, show that this compound can be used as the inhibitor of stromatin enzyme, thereby can be used to treat cancer, sacroiliitis, body ulcer, the medicine of diseases such as pulmonary emphysema, blood vessel scleratheroma.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
Synthesizing of 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-butyric acid (1)
1. aluminum chloride (10mmol) and bromobenzene (2mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (1.8mmol/10ml) of Succinic Acid lactone again.Naturally rise to room temperature, reheat refluxed 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated water chloroform extraction three times.Merge organic phase, and use saturated common salt water washing, anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets product 4-(4-bromophenyl)-4-oxidation-1-butyric acid through column chromatography.Productive rate 79%; 1HNMR (300MHz, CDCl 3): δ 7.86 (d, J=8.6Hz, 2H), 7.63 (d, J=8.6Hz, 2H), 3.28 (t, J=6.6Hz, 2H), 2.81 (t, J=6.5Hz, 2H); EIMS (m/z): 256 (M +), 183,155.
2. compound 4-(4-bromophenyl)-4-oxidation-1-butyric acid (25.4mmol) is dissolved among the saturated MeOH/HCl of 100mL stirring at room 12 hours.After reacting completely, remove solvent under reduced pressure, the residuum acetic acid ethyl dissolution is used the saturated common salt water washing, anhydrous Na again 2SO 4Dry.Remove solvent under reduced pressure, resistates gets product 4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography.Productive rate 84.4%. 1HNMR(300MHz，CDCl 3)：δ7.85(d，J＝8.0Hz，2H)，7.63(d，J＝7.8Hz，2H)，3.72(s，3H)，3.29(t，J＝6.5Hz，2H)，2.78(t，J＝6.3Hz，2H)；EIMS(m/z)：270(M +)，272(M ++2)，183。
3. under argon shield, 1-phenylacetylene (20mmol) and compound 4-(4-bromophenyl)-4-oxidation-methyl-butyrate are mixed in 50mL DMF and the 5mL triethylamine, add dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-methyl-butyrate through column chromatography.Productive rate 96%; 1HNMR (300MHz, CDCl 3): δ 7.98 (d, J=10.0Hz, 2H), 7.62 (d, J=10.8Hz, 2H), 7.56 (m, 2H), 7.39 (m, 3H), 3.72 (s, 3H), 3.33 (t, J=6.7Hz, 2H), 2.79 (t, J=6.7Hz, 2H); EIMS (m/z): 292 (M-), 205,176; HRMS (m/z) found292.11014 C 19H 16O 3Required 292.10995.
4. substrate 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-methyl-butyrate is dissolved in the methyl alcohol, adds 20% aqueous sodium hydroxide solution again, stirring at room.After reacting completely, transfer PH=1, use chloroform extraction again three times with 2M hydrochloric acid.Merge organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product 4-(4-phenylacetylene base)-phenyl-4-oxidation-1-butyric acid through column chromatography.Productive rate 52%. 1HNMR(300MHz，CDCl 3)：δ7.96(d，J＝8.5Hz，2H)，7.61(d，J＝8.5Hz，2H)，7.53(m 2H)，7.36(m，3H)，3.30(t，J＝6.5Hz，2H)，2.81(t，J＝6.5Hz，2H)；EIMS(m/z)：278(M +)，205，176；HRMS(m/z)found 278.09179 C 18H 16O 3 required278.09430.
Embodiment 2
(S) 4-(4-3-methoxyl group-1-proyl)-phenyl-4-oxidation-2-methoxycarbonyl amino-1-tert-butyl acetate (7) is synthetic
1. aluminum chloride (10mmol) and bromobenzene (2mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (1.8mmol/10ml) of compound (R)-3-methoxycarbonyl amino-succinic acid lactone again.Naturally rise to room temperature, reheat refluxed 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated water chloroform extraction three times.Merge organic phase, and use saturated common salt water washing, anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets product (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-butyric acid, productive rate 67% through column chromatography; [α] 20 D75.6 (c 3.8, CHCl 3); 1HNMR (300MHz, CDCl 3): δ 7.79 (d, J=8.2Hz, 2H), 7.61 (d, J=8.3Hz, 2H), 5.91 (br, 1H), 4.73 (m, 1H), 3.75 (m, 1H), 3.67 (s, 3H), 3.56 (m, 1H); EIMS (m/z): 329 (M +), 284,183; HRMS (m/z): found 328.99471, C 12H 12BrNO 5Requires 328.98088.
2. (5.0g 15.2mmol) is dissolved in the 70mL trimethyl carbinol, adds Boc then with compound (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-butyric acid 2O (3.82g, 7.5mmol) and DMAP (100mg).Stirring at room 3 hours, reaction removes solvent under reduced pressure, residuum acetic acid ethyl dissolution, water, saturated common salt water washing successively again, anhydrous Na after finishing 2SO 4Dry.Remove solvent under reduced pressure, resistates gets (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-tert-butyl acetate, 5.58g, productive rate 95.3% through column chromatography.[α] 26 D26.6(c 1.20，CHCl 3)； 1HNMR(300MHz，CDCl 3)：δ7.81(d，J＝8.6Hz，2H)，7.632(d，J＝8.4Hz，2H)，5.74(br，1H)，4.64(m，1H)，3.67(s，3H)，3.61(dd，J＝17.6，4.0Hz，1H)，3.43(dd，J＝17.6，4.3Hz，1H)，1.43(s，9H)；EIMS(m/z)：286(M +-COOt-Bu)，185。
3. under argon shield, 3-methoxyl group-1-propine (20mmol) and compound (s)-2-(methoxycarbonyl) amino-4-(4-bromophenyl)-4-oxidation-tert-butyl acetate are mixed in 50mL DMF and the 5mL triethylamine, add dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (S) 4-(4-3-methoxyl group-1-proyl)-phenyl-4-oxidation-2-methoxycarbonyl amino-1-tert-butyl acetate, productive rate 93% through column chromatography; [α] 26 D16.7 (c 0.66, CHCl 3); 1HNMR (300MHz, CDCl 3): δ 7.89 (d, J=8.3Hz, 2H), 7.54 (d, J=8.3Hz, 2H), 5.55 (br, 1H), 4.60 (t, J=4.2Hz, 1H), 4.34 (s, 2H), 3.67 (, m, 1H), 3.64 (s, 3H), 3.46 (s, 3H), 3.43 (m, 1H), 1.42 (s, 9H); EIMS (m/z): 376 (M ++ 1), 320,302; HRMS (m/z) found 302.10371 (C 20H 25NO 5-OC 4H 9) required 302.10284.
Embodiment 3
(+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-butyric acid (19) synthetic
1. aluminum chloride (20mmol) and bromobenzene (10mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, again the dichloromethane solution of dripping bromine acetyl bromide (10mmol/10ml) slowly.Naturally rise to room temperature, continue to stir 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated saturated common salt water washing, anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets product 4-bromophenyl-brooethyl ketone through column chromatography, yield about 75%. 1HNMR(300MHz，CDCl 3)：δ7.79(d，J＝10.9Hz，2H)，7.57(d，J＝10.8Hz，2H)，4.33(s，2H)；EIMS(m/z)：274(M +)，276，278。
2. (2.50g 14.0mmol) is dissolved in the 100mL tetrahydrofuran (THF) α-ethylbenzene methyl acetate compound (+/-).Under the argon shield this solution is chilled to-78 ℃, slowly add again LDA (1.0M, 15mL, 15.0mmol).Under this temperature, continuing to stir 1 hour, slowly add the tetrahydrofuran solution (4.1g, 15.0mmol in 40mL THF) of compound 4-bromophenyl-brooethyl ketone again. reaction mixture continues to stir 1 hour at-78 ℃, rises to room temperature again, continues to stir 8 hours.After reacting completely, in reaction mixture, add 150mL saturated aqueous ammonium chloride cancellation reaction.Add the saturated NaCl aqueous solution of 150mL again, ethyl acetate (250mL) is extracted.The organic phase anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets 4.5g (85.7%) alkylate (+/-) 2-ethyl-2-phenyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography. 1HNMR(300MHz，CDCl 3)：δ7.85(d，J＝8.5Hz，2H)，7.61(d，J＝8.5Hz，2H)，7.36`7.25(m，5H)，3.77(s，2H)，3.30(s，3H)，2.39~2.22(m，2H)，0.67(t，J＝7.5Hz，3H)；EIMS(m/z)：375(M ++1)，377，314，316，185，187。
3. under argon shield, 3-hydroxyl-1-propine (20mmol) and compound (+/-) 2-ethyl-2-phenyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate is mixed in 50mL DMF and the 5mL triethylamine, adds dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-methyl-butyrate, productive rate 46% through column chromatography. 1HNMR(300MHz，CDCl 3)：δ7.92(d，J＝7.8Hz，2H)，7.51(d，J＝8.1Hz，2H)，7.38~7.25(m，5H)，4.57(d，J＝5.5Hz，2H)，3.79(s，2H)，3.66(s，3H)，2.37~2.29(m，2H)，0.69(t，J＝7，5Hz，3H)；EIMS(m/z)：351(M ++1)，290，159；HRMS(m/z)found 350.15214 C 22H 22O 4 required 350.14984。
4. substrate (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-methyl-butyrate is dissolved in the methyl alcohol, adds 20% aqueous sodium hydroxide solution again, stirring at room.After reacting completely, transfer PH=1, use chloroform extraction again three times with 2M hydrochloric acid.Merge organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(4-3-hydroxyl-1-proyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-butyric acid, productive rate 83% through column chromatography. 1HNMR(300MHz，CDCl 3)：δ7.92(d，J＝7.5Hz，2H)，7.50(d，J＝7.6Hz，2H)，7.42~7.25(m，5H)，4.52(s，2H)，3.80(m，2H)，2.34~2.25(m，2H)，0.72(t，J＝7.0Hz，3H)；EIMS(m/z)：337(M ++1)，319，263，174，159；HRMS(m/z)found 318.12426(C 21H 20O 4-H 2O)required 318.12559.
Embodiment 3
(+/-) 4-(the positive decynyl of 4-1-)-phenyl-4-oxidation-3-ethyl-1-methyl-butyrate (16) synthetic
1. aluminum chloride (20mmol) and bromobenzene (10mmol) are blended in the 50mL methylene dichloride, ice bath is cooled to 0 ℃, slowly drips the dichloromethane solution (10mmol in 10ml) of n-butyryl chloride again.Naturally rise to room temperature, continue to stir 24 hours.After reacting completely, reaction mixture is poured in the mixture that is made into by 30g ice and 50mL 3M hydrochloric acid, stirred 1 hour.Organic phase is separated saturated common salt water washing, anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets product 4-bromophenyl-n-propyl ketone through column chromatography, yield about 75% 1HNMR (300MHz, CDCl 3): δ 7.83 (d, J=10.7Hz, 2H), 7.60 (d, J=10.6Hz, 2H), 2.91 (t, J=7.3Hz, 2H), 1.80 ~ 1.67 (m, 2H), 1.00 (t, J=7.4Hz, 3H); EIMS (m/z): 220 (M +), 222,185,183.
2. (3.00g 13.6mmol) is dissolved in the 100mL tetrahydrofuran (THF) compound 4-bromophenyl-n-propyl ketone.Under the argon shield this solution is chilled to-78 ℃, slowly add again LDA (1.0M, 15mL, 15.0mmol).Under this temperature, continuing to stir 1 hour, slowly add the tetrahydrofuran solution (2.1g, 14.0mmol in 12mL THF) of methyl bromoacetate again. reaction mixture continues to stir 1 hour at-78 ℃, rises to room temperature again, continues to stir 8 hours.After reacting completely, in reaction mixture, add 50mL saturated aqueous ammonium chloride cancellation reaction.Add the saturated NaCl aqueous solution of 50mL again, ethyl acetate (250mL) is extracted.The organic phase anhydrous Na 2SO 4Dry.Remove solvent under reduced pressure, resistates gets 3.3g (81.5%) alkylate (+/-) 3-ethyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate through column chromatography. 1HNMR(300MHz，CDCl 3)：δ7.78(d，J＝10.8Hz，2H)，7.55(d，J＝10.6Hz，2H)，3.72(M，1H)，3.40(S，3H)，2.88(DD，J＝17.0，9.5Hz，1H)，2.44(，dd，J＝17.0，4.7Hz，1H)，1.71~1.42(m，2H)，0.81(t，J＝7.3Hz，3H)；EIMS(m/z)：298(M +)，299。
3. under argon shield, positive decine (20mmol) and compound (+/-) 3-ethyl-4-(4-bromophenyl)-4-oxidation-methyl-butyrate is mixed in 50mL DMF and the 5mL triethylamine, adds dichloro two triphenyl phosphorus palladiums (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) again.Then, being heated to 75 ℃ stirred 24 hours.After reacting completely, add methyl alcohol 15mL cancellation reaction.Remove solvent under reduced pressure, residuum acetic acid ethyl dissolution, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates gets product (+/-) 4-(the positive decynyl of 4-1-)-phenyl-4-oxidation-3-ethyl-1-methyl-butyrate, productive rate 76.6% through column chromatography. 1HNMR(300MHz，CDCl 3)：δ7.82(d，J＝10.8Hz，2H)，7.41(d，10.6Hz，2H)，3.73(m，1H)，3.43(s，3H)，2.98(dd，J＝17.0，4.7Hz，1H)，2.61~2.47(m，3H)，1.78~0.86(m，17H)；EIMS(m/z)：356(M +)，241；HRMS(m/z)found 356.23524 C 23H 32O 3 required 356.23514。
Embodiment 4
Compound of the present invention has been tested the inhibition activity of these compounds to the stromatin enzyme through the Ye Qizhuan researcher at Shanghai Pharmaceutical Inst., Chinese Academy of Sciences national drug screening center.These compounds have been tested to MMP-1 (collagenase-1), MMP-3 (matrix lytic enzyme-1), MMP-9 (gelatinase-B), MMP-12 (scavenger cell elastoser), MMP-13 (collagenase-3), MMP-15 (membranous type 2-MMPs), the restraining effect of MMP-16 (membranous type 3-MMPs), the result is as shown in the table.
The gamma-carbonyl group benzenebutanoic acid compounds that table 14-replaces is to the inhibition activity of matrix metalloproteinase
Compound IC50(μM)
MMP-1 MMP-3 MMP-9 MMP-12 MMP-13 MMP-15 MMP-16
2 3 4 5 10 11 12 13 14 15 17 18 19 20 21 22 ＞83.25 54.331 ＞83.25 40.440 ＞83.25 ＞83.25 ＞83.25 ＞83.25 52.146 ＞83.25 33.211 ＞83.25 ＞83.25 ＞83.25 ＞83.25 5.530 10.990 3.188 68.776 47.150 ＞83.25 ＞83.25 5.323 17.884 6.096 ＞83.25 ＞83.25 ＞83.25 ＞83.25 50.006 ＞83.25 26.332 ＞83.25 ＞83.25 ＞83.25 ＞83.25 17.672 15.023 5.537 ＞83.25 ＞83.25 ＞83.25 ＞6.25 1.65 ＞6.25 0.167 ＞6.25 ＞6.25 ＞6.25 ＞83.25 3.857 ＞83.25 4.340 ＞83.25 ＞83.25 ＞83.25 ＞83.25 6.099 82.279 4.812 37.659 ＞83.25 ＞83.25 ＞83.25 3.753 21.681 3.371 ＞83.25 ＞83.25 ＞83.25 72.557 ＞83.25 0.762 87.715 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 36.255 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 ＞83.25 31.156 15.330 31.382 ＞83.25 ＞83.25 ＞83.25 ＞83.25 46.348 ＞83.25 ＞83.25 ＞83.25 ＞83.25
By the table in as can be seen, the gamma-carbonyl group benzenebutanoic acid compounds of synthetic 4-alkynyl substituted has better inhibited activity to matrix metalloproteinase.They can optionally suppress MMP-3, MMP-9, MMP-12, and to almost not influence of MMP-1, MMP-13, MMP-15 and MMP-16.4 alkynyl substituted bases of this compounds are to have MMP-3, MMP-9, the inhibiting necessary group of MMP-12.And increase and the lipotropy enhancing along with 4 alkynyl substituted matrixes are long-pending, its inhibition activity to MMP-3, MMP-12 also obviously strengthens, and lipotropy weakens, and obviously strengthens the inhibition of MMP-9 is active.Substituting group is introduced in β position at ester group, can improve their inhibition activity to MMP-3, MMP-12, and introduces substituting group in ester group α position, then causes and suppresses active reduction even disappearance.Alkoxycarbonyl amido is introduced in α position at ester group, can improve the inhibition activity to MMP-3, MMP-12.

Claims (8)

1. one kind (4-alkynyl)-aryl ketones acid compounds, it has following structural formula:
Figure C021115150002C1
Wherein R is H or C 1-10Alkyl; R 1Be H, C 1-10Alkyl, CH 2OR 5, CH 2OH, OBn, OH or OCH 3R 2Be H, C 1-6Straight chain or have the alkyl of side chain; R 3Or/and R 4Be H, OH, OR 5, NHCOOR 5, C 2H 5Or Ph; R 5Be C 1-10Alkyl; Described alkyl is straight chained alkyl, have the alkyl of side chain or aryl, aryl or substituted aryl.
2. a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that having following structural formula:
Figure C021115150002C2
Figure C021115150003C1
3. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that synthetic respectively by the following method:
1) in polar organic solvent, the R that chirality replaces 2And/or R 3Succinic Acid lactone, halogeno-benzene and lewis acidic mol ratio are 1: 1-1.5: during 3-7, under the Lewis acid effect, backflow 16-36 hour, the Fu Ke acidylate takes place generate R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces
Perhaps R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality replaces;
2) in the organic solvent and Louis acid catalysis under, halogeno-benzene and
Figure C021115150003C3
Room temperature reaction 16-24 hour, the generation molecular formula was
Figure C021115150003C4
4-halogenophenyl ketone, wherein halogeno-benzene, With lewis acidic mol ratio be 1: 1-2: 1-3;
At-78 ℃-room temperature and C 1-8The lithium alkylide effect under, 4-halogenophenyl ketone and alpha-halogen acid esters XCH 2Alkylated reaction takes place in COOR, reacts 5-20 hour, obtains R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid meso compound that replaces Wherein 4-halogenophenyl ketone, alpha-halogen acid esters and C 1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;
R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces;
3) in polar organic solvent under the Lewis acid effect, halogeno-benzene and halo acetyl halide With lewis acidic mol ratio be 1: 1-1.5: during 3-7, the Fu Ke acidylate took place generate halo ethanoyl halogenophenyl ketone in backflow 16-36 hour;
At-78 ℃-room temperature and C 1-8The lithium alkylide effect under, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester PhCH (C 2H 5) alkylated reaction takes place COOR, react to obtain R in 5-20 hour 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces Wherein, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester and C 1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;
Perhaps by R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that replaces and saturated alcohol roh/hydrochloric acid room temperature reaction 1-10 hour can become corresponding R 2And/or R 34-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.
4) 4-of Qu Daiing (4-halogenophenyl)-4-oxidation-butyric acid with saturated alcohol roh/hydrochloric acid room temperature reaction 10-1 hour, becomes 4-(4-halogenophenyl)-4-oxidation-butyric ester
Figure C021115150004C3
In organic polar solvent, 4-(4-halogenophenyl)-4-oxidation-butyric ester, corresponding alkynes CH ≡ CR 1, contain the organic compound acid binding agent and the catalyzer of lone-pair electron on the nitrogen, 4 alkynyls are introduced in 50-100 ℃ of reaction 16-36 hour, gamma-carbonyl group benzenebutanoic acid compounds that must the 4-alkynyl substituted
Figure C021115150004C4
Wherein 4-(4-halogenophenyl)-4-oxidation-butyric ester, alkynes CH ≡ CR 1With the mol ratio of acid binding agent be 1: 1-3: 0.01-0.15, the weight ratio of 4-(4-halogenophenyl)-4-oxidation-butyric ester and catalyzer is 1: 0.001-0.010, described catalyzer is dichloro two triphenyl phosphorus palladiums, cuprous iodide, tetrabutylammonium iodide or their mixture
5) above-mentioned R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric acid that chirality or achirality replace is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets esterification and gets R 2And/or R 34-(4-halogenophenyl)-4-oxidation-butyric ester that chirality or achirality replace.
4. the synthetic method of described a kind of (4-the alkynyl)-aryl ketones acid compounds of claim 3 is characterized in that wherein 2) and 3) reaction be under the anhydrous and oxygen-free condition He in the tetrahydrofuran solution, to carry out.
5. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3, the organic compound acid binding agent that it is characterized in that containing on the described nitrogen lone-pair electron is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.
6. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3 is characterized in that described C 1-8Lithium alkylide be butyllithium, di-isopropyl lithium, octyl group lithium.
7. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that the inhibitor of stromatin enzyme.
8. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 7 is characterized in that a kind of treatment cancer,, the medicine of sacroiliitis, body ulcer, pulmonary emphysema or blood vessel scleratheroma disease.
CNB02111515XA 2002-04-26 2002-04-26 (4-alkynyl), aromatic keto-acid compound, synthesis method and its application Expired - Fee Related CN1169768C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB02111515XA CN1169768C (en) 2002-04-26 2002-04-26 (4-alkynyl), aromatic keto-acid compound, synthesis method and its application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB02111515XA CN1169768C (en) 2002-04-26 2002-04-26 (4-alkynyl), aromatic keto-acid compound, synthesis method and its application

Publications (2)

Publication Number Publication Date
CN1380279A CN1380279A (en) 2002-11-20
CN1169768C true CN1169768C (en) 2004-10-06

Family

ID=4741606

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB02111515XA Expired - Fee Related CN1169768C (en) 2002-04-26 2002-04-26 (4-alkynyl), aromatic keto-acid compound, synthesis method and its application

Country Status (1)

Country Link
CN (1) CN1169768C (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009115534A1 (en) 2008-03-19 2009-09-24 Novartis Ag Process for the preparation of 2-amino-2- [2- (4-c3-c21-alkyl-phenyl)ethyl] propane-1, 3-diols
KR101821646B1 (en) * 2010-10-27 2018-01-25 프로메틱 파마 에스엠티 리미티드 Compounds and compositions for the treatment of cancer
CN110330420B (en) * 2019-07-31 2020-07-10 湖南大学 Process for preparing acids with different substituents

Also Published As

Publication number Publication date
CN1380279A (en) 2002-11-20

Similar Documents

Publication Publication Date Title
JP6181747B2 (en) Catechol O-methyltransferase activity inhibiting compound
EP3260463B1 (en) Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
RU2365580C2 (en) Levodop prodrugs, based on them compositions and their application
EP1477472B1 (en) Substituted phenylalkanoic acid derivative and use thereof
EP1404685B1 (en) Aryl boronic acids for treating obesity
KR20160047378A (en) Novel aminoalkylbenzothiazepine derivatives and use thereof
TWI821328B (en) Novel compounds
CN1310721A (en) Medicine nitrate salts
CN111183129B (en) Novel anthranilic acid compound, pin1 inhibitor using same, and therapeutic agent for inflammatory disease and cancer
EP4043455A1 (en) Bicyclic compound that acts as crbn protein regulator
CN111448182A (en) Aztreonam derivative and application thereof
CN1169768C (en) (4-alkynyl), aromatic keto-acid compound, synthesis method and its application
CN107698521B (en) Preparation and application of 5-fluorouracil substituted carboxylic acid derivative
US20190031676A1 (en) Antibacterial annulated pyrrolidin-2-one derivatives
KR101748229B1 (en) 2,2&#39;-bis-thiazole-based compounds, preparation method therefor and use thereof
EP0787135A1 (en) Water-soluble epipodophyllotoxin derivatives, preparation method therefor, and use thereof as a drug and for treating cancer
CN1169727A (en) Erythromycin A 9-0-oxime derivatives endowed with antibiotic activity
RU2006114673A (en) NEW DERIVATIVES 4A, 5,9,10,11,12-HEXAHYDROBENZENOFURO- [3A, 3.2] [2] BENZAZEPINE, METHOD FOR PRODUCING THEM, AND ALSO APPLICATION FOR PRODUCING MEDICINES
WO2008116387A1 (en) A preparation process for taxol and derivatives thereof
JPH10502050A (en) N-[{4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracen-yl} carbonyl] amino acids useful in the treatment of osteoarthritis
CN114380888B (en) Difluoro substituted romidepsin analogue, preparation method and application thereof
CN113402414A (en) Benzoic acid derivative and preparation method and pharmaceutical application thereof
WO2022040788A1 (en) Open-ring and lactone derivatives of unsaturated trihydroxy c-18 fatty acids and pharmaceutical compositions thereof having anti-cancer activity
FR2478629A1 (en) 2-CYANO-ETHYL-2- (N-BENZOYLAMINO) ALKANOIC ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
CN114920663A (en) Bibenzol oseltamivir derivative as well as preparation method and application thereof

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20041006

Termination date: 20110426